Department of Breast and Thyroid Surgery, Wuhan University Renmin Hospital, Wuhan, China.
Planta Med. 2011 Jan;77(2):141-5. doi: 10.1055/s-0030-1250179. Epub 2010 Aug 17.
The involvement of unfolded protein response (UPR) activation in tumor survival and resistance to chemotherapies suggests a new anticancer strategy targeting UPR pathway. Arctigenin, a natural product, has been recently identified for its antitumor activity with selective toxicity against cancer cells under glucose starvation with unknown mechanism. Here we found that arctigenin specifically blocks the transcriptional induction of two potential anticancer targets, namely glucose-regulated protein-78 (GRP78) and its analog GRP94, under glucose deprivation, but not by tunicamycin. The activation of other UPR pathways, e.g., XBP-1 and ATF4, by glucose deprivation was also suppressed by arctigenin. A further transgene experiment showed that ectopic expression of GRP78 at least partially rescued arctigenin/glucose starvation-mediated cell growth inhibition, suggesting the causal role of UPR suppression in arctigenin-mediated cytotoxicity under glucose starvation. These observations bring a new insight into the mechanism of action of arctigenin and may lead to the design of new anticancer therapeutics.
未折叠蛋白反应 (UPR) 的激活参与肿瘤的存活和对化疗药物的耐药性，这表明针对 UPR 途径的一种新的抗癌策略。牛蒡子苷元是一种天然产物，最近因其在葡萄糖饥饿条件下对癌细胞具有选择性毒性的抗肿瘤活性而被鉴定出来，但具体机制尚不清楚。在这里，我们发现牛蒡子苷元在葡萄糖剥夺条件下特异性地阻断了两个潜在的抗癌靶点，即葡萄糖调节蛋白-78 (GRP78)及其类似物 GRP94 的转录诱导，而不是通过衣霉素。葡萄糖剥夺还抑制了其他 UPR 途径的激活，如 XBP-1 和 ATF4。进一步的转基因实验表明，GRP78 的异位表达至少部分挽救了牛蒡子苷元/葡萄糖饥饿介导的细胞生长抑制，这表明在葡萄糖饥饿条件下，UPR 抑制在牛蒡子苷元介导的细胞毒性中起因果作用。这些观察结果为牛蒡子苷元的作用机制提供了新的见解，并可能导致新的抗癌治疗方法的设计。
